Prophylactic immune priming with heat-killed Lacticaseibacillus rhamnosus combined with therapeutic Lactiplantibacillus plantarum cell-free supernatant protects against Pseudomonas aeruginosa lung infection in mice

Background: is a leading cause of severe respiratory infections in immunocompromised individuals, and its increasing antibiotic resistance poses a major global health challenge. Antibiotic-resistant strains exhibit enhanced biofilm-forming capacity, contributing to persistent infection, immune evasion, and poor clinical outcomes. Innovative non-antibiotic strategies that simultaneously enhance host immunity and directly target bacterial virulence are urgently needed. Methods: . HK1505 and LpCFS treatments were evaluated separately and in combination. Results: CRL1505 and notably, HK1505 retained the immunostimulatory efficacy of the viable bacteria. In addition, the combination of the prophylactic HK1505 administration and the therapeutic LpCFS treatment provided superior protection against the respiratory infections than individual treatments. The combined approach completely prevented lung infection and bacteremia in PaS-infected mice and significantly improved the outcomes in PaR infection. Conclusion: lung infection. This approach highlights the translational potential of postbiotic immunomodulation as a safe and innovative alternative for managing multidrug-resistant respiratory infections.